Alzheimer's disease is a neurodegenerative disorder that is the most frequent cause of dementia among aged individuals. The disease is characterized by the accumulation of amyloid-containing plaques in the brain, particularly in the temporal cortex and hippocampus and along the walls of the cerebral vasculature (Roch et al., 1966, Nature 209: 109-110; Terry et al., 1981, Ann. Neurol. 10: 184-192; Glenner G. G., 1983, Arch. Pathol. Lab. Med. 107: 281-282; Katzman, R., 1983, Banbury Report 15, Cold Spring Harbor Lab., Cold Spring, N.Y.).
The amyloid peptide (.beta.A4), found in the plaques of the brain derives from a protein referred to as the amyloid (or beta-amyloid) precursor protein (.beta.APP). .beta.APP is normally cleaved within the amyloid domain, which lies near its C-terminus, so that no intact amyloid is produced. An alternative processing pathway results in cleavage of .beta.APP N-terminal to the amyloid domain, releasing the entire C-terminal from which intact amyloid peptide (.beta.A4) of the amyloid protein precursor may be produced (Glenner and Wong, 1984, Biochem Biophys Res. Commun. 120: 885-890; Masters et al., 1985, Proc. Natl Acad. Sci. USA 82: 4245-4249).
Recent evidence suggests that aberrant processing of .beta.-APP underlies the neuronal degeneration that occurs in Alzheimer's Disease. Neve and coworkers have proposed that the primary .beta.APP processing event in Alzheimer's Disease is cleavage of the amino terminus of the .beta./A4 sequence, producing a carboxy-terminal .beta.APP fragment of 100 amino acid residues (.beta.APP-C100) which was expressed from a cDNA sequence encoding the carboxyterminal 104 amino acids of .beta.APP (Yankner et al., 1989, Science 245: 417-420). Hereinafter, this fragment of .beta.APP will be referred to as .beta.APP-C100 regardless of whether it is expressed from a cDNA encoding the carboxyterminal 100 or 104 amino acid residues of .beta.APP. Expression of the .beta.APP-C100 peptide in primate cells has been shown to lead to production of a protein that aggregates and accumulates into deposit-like structures that result in formation of amyloid-like fibrils (Wolf et al., 1990 EMBO J. 9: 2079-2084). A retroviral recombinant which directs the expression of .beta.APP-C100 has also been shown to be neurotoxic when transfected into PC-12 cells that have been induced to differentiate by addition of NGF (nerve growth factor). Furthermore, the conditioned media from these transfected cells is toxic to differentiated neuroblastoma and neural cells, and the neurotoxicity can be removed from the medium by immunoabsorption with an antibody to .beta.APP-C100 suggesting that .beta.APP-C100 is secreted by transfected cells and is neurotoxic (Yankner et al., 1989, Science 245: 417-420). The toxicity of .beta.APP-C100 has been further demonstrated by transplantation of cells expressing the peptide into the brains of newborn mice and by creation of mice transgenic for human .beta.APP-C100 (Neve et al., 1992, Proc. Natl. Acad. Sci. USA 89: 3448-3452). Taken together, evidence indicates a role for .beta.APP-C100 in development of the neurodegeneration in Alzheimer's disease.
Despite the intense interest in the .beta.APP-C100 peptide, and its biological role in development of Alzheimer's Disease, very little is known about the proteins, receptors or other tissue elements with which the .beta.APP-C100 peptide interacts to produce neurotoxicity. Very recently, the high affinity binding of .beta.APP-C100 to the surface of differentiated PC-12 cells has been demonstrated and correlated with neurotoxicity (Kozlowski et al., 1992, J. of Neuroscience 12: 1679-1687). Both the binding interaction and the occurrence of the neurotoxic response have the same pH dependence. In addition, in PC-12 cells, both the binding and the susceptibility to neurotoxicity develop with similar time courses during NGF-induced differentiation. Furthermore, a single amino-acid change in the .beta.APP-C100 peptide (Tyr.sub.687 to Phe), which eliminates its neurotoxic effect, also produces a loss of binding potency. However, the molecular species responsible for binding has not been identified or characterized. The isolation of a cDNA clone coding for the .beta.APP-C100 binding site or receptor would facilitate studies aimed at determining the biological function of C100-R and its role in development of Alzheimer's Disease. However, this has not, heretofore, been accomplished.